Rheumatoid arthritis (RA) is a chronic destructive inflammatory disease of unknown etiology, which affects the joints. Histopathologic examination of the rheumatoid pannus reveals hyperplasia of synovial lining cells, along with a mononuclear cell infiltrate that includes primarily T cells. The present application proposes to examine the possibility that excessive accumulation of lymphocytes and synovial cells in the rheumatoid pannus is a result of their resistance to programmed cell death (apoptosis). The hypothesis is based on recent preliminary studies by the investigators, which uncovered a sphingomyelin pathway-mediated inhibition of Fas death signaling in lymphocytes and synoviocytes of RA patients. In addition, in preliminary studies the investigators have demonstrated a role for a Gi protein-coupled receptor-mediatred activation of phosphatidylinositol-3-kinase (PI3K) in regulating the sphingomyeline pathway. Inhibition of those mechanisms reversed the signaling aberration and restored susceptibility to Fas-mediatred cell death in previously resistant RA cells. The proposed research has four specific aims: 1. To further define the receptors involved 2. To determine the mechanisms of PI3K hyperactivity 3. To map sphingomyelin pathway defect 4. To determine clinical and HLA correlates with those signaling defects The proposed research takes a novel experimental approach to study the pathogenesis of RA, based on modern concepts in autoimmunity and cutting edge methodologies. The proposed studies will likely contribute significantly to understanding the pathogenesis of RA and, perhaps, other autoimmune diseases.